A 52-week, randomised, double blind, multicentre, 2-arm parallel group trial assessing the efficacy and safety of CHF6001 (total daily dose 3200 μg) Dry Powder Inhaler (DPI) add-on to maintenance medium or high dose inhaled corticosteroid in combination with long-acting ß2-agonists in subjects with uncontrolled asthma

Trial ID: 2022-502208-64-00
Protocol: CLI-06001AA2-01
Sponsor: Chiesi Farmaceutici S.p.A.

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Diseases & Conditions

Asthma

Objectives

The primary objective of this study is to assess the **efficacy** of CHF6001 at a total daily dose of 3200 µg compared to placebo. This is evaluated as an add-on to maintenance medium-to-high dose inhaled corticosteroid/long-acting β2-agonist (ICS/LABA) combination therapy in reducing the rate of **asthma exacerbations** over a 52-week treatment period. This objective is clinically relevant as it aims to determine the potential of CHF6001 to improve asthma control and reduce exacerbations, which are critical outcomes for patients with uncontrolled asthma.

Secondary objectives include:

Evaluating the efficacy of CHF6001 3200 µg total daily dose compared to placebo in terms of lung function, Asthma Control Questionnaire©-7 (ACQ-7), health-related quality of life, and other clinical outcome measures.
Assessing the safety and tolerability of the study treatment versus placebo.

These secondary objectives are important for understanding the broader impact of CHF6001 on patient health and safety, beyond the primary endpoint of exacerbation reduction.

Participants

The clinical trial involves a total of **142 participants** diagnosed with **asthma**. The study population includes both male and female subjects aged between 18 and 75 years. Participants were selected based on their documented history of physician-diagnosed asthma for at least one year, with the diagnosis made before the age of 50. All participants are required to have been on a stable maintenance treatment with a fixed combination of medium to high dose inhaled corticosteroid and long-acting β2-agonist for at least three months prior to screening. The trial includes individuals with evidence of poorly controlled asthma, as indicated by an Asthma Control Questionnaire score of 1.5 or higher, and a history of asthma exacerbations within the last 12 months. Participants must demonstrate bronchodilator responsiveness and have a prebronchodilator forced expiratory volume in the first second of 80% or less of the predicted normal value. The trial population is characterized by a cooperative attitude and the ability to correctly use inhalers, perform trial-related procedures, and utilize an electronic diary and home spirometer. The study does not exclude vulnerable populations, and both genders are represented. Lifestyle considerations such as diet and physical activity are not specified by the sponsor.

Plans and Procedures

The clinical trial is designed as a **randomized**, **double-blind**, controlled study to evaluate the efficacy and safety of CHF6001, an **inhalation powder** containing the active substance **tanimilast**, in subjects with uncontrolled **asthma**. The trial will span a duration of 52 weeks, during which participants will be randomly assigned to receive either CHF6001 or a matching placebo as an add-on to their existing maintenance therapy of medium-to-high dose inhaled corticosteroids combined with long-acting β2-agonists. The primary objective is to assess the reduction in the rate of asthma exacerbations over the treatment period.

Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, asthma diagnosis, and current treatment regimen. Following successful screening, participants will be randomized and commence the treatment phase. Follow-up visits will occur at regular intervals to monitor safety, efficacy, and adherence to the study protocol. These visits will include assessments such as lung function tests, asthma control questionnaires, and recording of any adverse events. The end-of-study visit will conclude the trial, where final evaluations will be conducted to assess the overall outcomes of the treatment.

The expected length of participant involvement is approximately 52 weeks, aligning with the trial's duration. Conditions that may lead to early termination from the study include non-compliance with the study protocol, withdrawal of consent, or the occurrence of significant adverse events that warrant discontinuation of the investigational product. The trial is structured to ensure rigorous monitoring and data collection, contributing to the comprehensive evaluation of CHF6001's potential benefits in managing uncontrolled asthma.

Treatment

The clinical trial involves the administration of **CHF6001 DPI**, an experimental medication formulated as an **inhalation powder**. The active substance in CHF6001 DPI is **tanimilast**, a chemical entity. The medication is delivered via the **NEXThaler®** device, which is not CE marked. The total daily dose of CHF6001 DPI is 3200 micrograms, administered through inhalation. The treatment period extends up to 52 weeks. The maximum total dose over the treatment period is 1,168,000 micrograms. The trial aims to evaluate the efficacy of CHF6001 DPI as an add-on therapy to maintenance medium or high-dose inhaled corticosteroids combined with long-acting beta2-agonists in subjects with uncontrolled asthma.

In addition to the experimental treatment, a **matching placebo** is used in the study. The placebo is designed to mimic the CHF6001 DPI in appearance and administration method but does not contain the active substance, tanimilast. The placebo serves as a comparator to assess the efficacy of the experimental treatment. Participants are randomly assigned to receive either the CHF6001 DPI or the matching placebo, ensuring a double-blind study design. Compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the treatment protocol.

Efficacy

The efficacy of the clinical trial will be assessed by evaluating the impact of CHF6001, an inhalation powder containing **tanimilast**, as an add-on therapy to maintenance medium or high dose inhaled corticosteroid in combination with long-acting β2-agonists in subjects with uncontrolled asthma. The primary endpoint for efficacy assessment is the number of asthma exacerbations over the 52-week study period. Secondary endpoints include the time to first asthma exacerbation, the number of asthma exacerbations and asthma worsening over 52 weeks, and the time to first asthma exacerbation or asthma worsening.

Additional secondary endpoints involve patient-reported outcomes and lung function measures. These include the Asthma Control Questionnaire (ACQ-7) responders at Week 4, Week 26, and Week 52, defined as subjects showing an improvement from baseline in ACQ-7 score of ≥0.5 units. Changes from baseline in ACQ-7 and ACQ-6 scores, Mini-Asthma Quality of Life Questionnaire (Mini-AQLQ) scores, pre-dose Forced Expiratory Volume in the first second (FEV1), and pre-dose Forced Vital Capacity (FVC) at specified timepoints (Week 4, Week 26, and Week 52) will also be measured. Furthermore, changes from baseline in pre-dose morning/evening Peak Expiratory Flow (PEF), average rescue medication use, and asthma symptoms score will be evaluated throughout the treatment period.

The efficacy parameters will be collected and analyzed at various timepoints, including Week 4, Week 26, and Week 52, using validated scales and patient-reported outcomes. The trial will utilize tools such as the electronic diary (e-Diary) and home spirometer to ensure accurate and consistent data collection. The study aims to provide a comprehensive assessment of the efficacy of CHF6001 in reducing asthma exacerbations and improving asthma control in the target population over the course of the trial.

Inclusion and Exclusion Criteria

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Inclusion Criteria

Informed consent: Subject’s written informed consent obtained prior to any study-related procedures
Sex and age: Male or female subjects aged ≥18 and ≤75 years
Diagnosis of asthma: A documented history of physician-diagnosed asthma for at least 1 year and with diagnosis before the age of 50 years
Stable asthma therapy: a stable maintenance treatment with fixed combination of medium to high dose of ICS plus LABA for at least 3 months prior to screening. Medium and high doses of ICS are defined according to Global Initiative for Asthma (GINA) 2022
Lung function: A prebronchodilator Forced expiratory volume in the first second (FEV1) ≤80% of the predicted normal value, after appropriate washout from bronchodilators, at the screening visit and at randomisation visit
Bronchodilator responsiveness: A demonstrated increase (>12% AND >200mL) in either FEV1 or Forced vital capacity (FVC) from baseline within 30 min after inhalation of 400 μg salbutamol (albuterol) or equivalent
Poor asthma control: Evidence of poorly controlled or uncontrolled asthma as based on Asthma Control Questionnaire (ACQ-7) score ≥1.5 at screening and at randomization
History of asthma exacerbations: A documented history of: - At least 1 asthma exacerbation leading to hospitalization within the last 12 months prior to screening; or - 2 or more asthma exacerbations within the last 12 months prior to screening, defined as a worsening of asthma symptoms that leads to any of the following: - an outpatient treatment with Systemic corticosteroids( SCS*); - an inpatient hospitalisation because of asthma; - an emergency room visit that resulted in the use of SCS*; * including oral or parenteral routes (a single depo-injectable dose of corticosteroid will be considered the equivalent to a 3-day course of SCS)
A cooperative attitude and ability: - to correctly use the inhalers; - to perform all trial-related procedures including technically acceptable spirometry; - to correctly use the electronic diary (e-Diary) and home spirometer;
Females are eligible to enter the study if they are of: - non-childbearing potential i.e. physiologically incapable of becoming pregnant (e.g. postmenopausal women defined as being amenorrhoeic for ≥12 consecutive months without an alternative medical cause) or women permanently sterilized. - Women of childbearing potential with fertile partners: they must have a negative pregnancy test at screening and they or/and their partners must agree to use 1 or more of the following acceptable contraceptive measures: - Placement of an intrauterine device or intrauterine hormone releasing system; - Combined (oestrogen and progesterone containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal); - Progesterone only hormonal contraception associated with inhibition of ovulation (oral, injectable,implantable); - Bilateral tubal occlusion; - Vasectomised partner; Reliable contraception should be maintained throughout the study. - Women of childbearing potential (WOCBP) with non-fertile male partners (contraception is not required in this case)

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Exclusion Criteria

Run-in compliance: e-Diary completion compliance <75% at randomization
History of “at risk” asthma: history of near fatal asthma or of a past hospitalisation for asthma in intensive care unit which, in the judgement of the Investigator, may place the subject at undue risk
Recent exacerbation or respiratory tract infection: hospitalisation, emergency room admission or use of SCS for an asthma exacerbation or a documented diagnosis of lower respiratory tract infection that required antibiotics or an unresolved respiratory tract infection within 4 weeks prior to screening visit or during the run-in period
Subjects using SCS medication in the 4 weeks or slow-release corticosteroids in the 12 weeks prior to randomization
Asthma requiring use of biologics: subjects currently receiving asthma treatment or having received treatment within 6 months prior to randomisation with injectable monoclonal antibodies (e.g.,omalizumab, dupilumab, mepolizumab, reslizumab, benralizumab, tezepelumab, etc.)
Respiratory disorders other than asthma: subjects with known respiratory disorders other than asthma. This can include but is not limited to: Chronic obstructive pulmonary disease (COPD), α1-antitrypsin deficiency, active tuberculosis, bronchiectasis, sarcoidosis, lung fibrosis, pulmonary hypertension, and interstitial lung disease
Lung resection: subjects with a history of lung volume resection
Smoking status: Current smoker (including e-cigarettes), ex-smoker with a smoking history of 10 pack-years (pack-years = the number of cigarette packs per day times the number of years), or current use of inhaled or oral cannabis products. Ex-smokers must have stopped smoking for ≥1 year (≥6 months for e-cigarettes)
Cancer or history of cancer: subjects with active cancer or a history of cancer with <5 years disease-free survival time (e.g., when there is evidence of local recurrence or metastases). Localised carcinoma (e.g., basal cell carcinoma, in situ carcinoma of the cervix adequately treated) is acceptable
Cardiovascular diseases: subjects who have a clinically significant (CS) cardiovascular condition according to Investigator’s judgement, such as but not limited to: congestive heart failure (New York Heart Association (NYHA) class IV); unstable or acute ischaemic heart disease in the last year prior to screening; history of sustained and non-sustained cardiac arrhythmias diagnosed in the last 6 months prior to screening and not controlled with a rate control strategy; high degree impulse conduction blocks (>2nd degree atrioventricular block type 2); persistent, long standing or paroxysmal atrial fibrillation
ECG criteria: any abnormal and CS 12-lead ECG that in the Investigator's opinion would affect efficacy or safety evaluation or place the subjects at risk. Male subjects with a QTcF >450 msec and female subjects with a QTcF >470 msec at screening are not eligible (not applicable for subjects with permanent atrial fibrillation and for subjects with pacemaker); not applicable for subjects for subjects with permanent atrial fibrillation and for subjects with pacemaker)
Previous medical history, evidence of an uncontrolled intercurrent illness, or any clinically relevant abnormal findings in haematology, clinical chemistry, or urinalysis that in the opinion of the Investigator and/or medical monitor may compromise the safety of the subject in the study or interfere with evaluation of the IMP or reduce the subject’s ability to participate in the study. Subjects with well-controlled comorbid disease (i.e.,hypertension, hyperlipidaemia, gastroesophageal reflux disease) on a stable treatment regimen for at least 15 days prior to screening are eligible; Subjects with a diagnosis of depression, generalised anxiety disorder, suicidal ideation or behaviour that may, according to the Investigator’s judgement, place the subject at undue risk
Subjects with a diagnosis of depression, generalised anxiety disorder, suicidal ideation or behaviour that may, according to the Investigator’s judgement, place the subject at undue risk
Patients mentally or legally incapacitated or patients accommodated in an establishment as a result of an official or judicial order
Liver diseases: subjects with severe hepatitis, chronic active hepatitis, or evidence of uncontrolled chronic liver disease according to the Investigator’s opinion
Drugs with hepatoxicity potential: subjects receiving treatment with any drug known to have a well-defined potential for hepatotoxicity (i.e., isoniazide, nimesulide, ketoconazole) and strong inhibitors of cytochrome P450 (CYP)3A4/5 (i.e.,itraconazole) within the previous 3 months before the screening visit
Contra-indications to IMP: Subjects with a history of allergy or hypersensitivity to β2-agonists, corticosteroids, phosphodiesterase-4 inhibitors or any of the excipients contained in any of the formulations used in the trial or a medical condition that in the Investigator’s opinion would contra-indicate study participation
Alcohol/drug abuse: Subjects with a known or suspected history of alcohol and/or drug abuse within 12 months prior to screening
Surgery: Subjects with major surgery (i.e., aortic and major vascular surgery, cystectomy, pneumonectomy, liver transplantation, oesophagostomy, duodeno-pancreatic surgery, etc.) in the 3 months prior to screening visit or planned during the trial; low-risk procedures are allowed during the trial (i.e., endoscopic procedures, cataract surgery, superficial breast surgery, partial mastectomy without lymph node dissection, etc.)
Subjects treated with non-potassium sparing diuretics (unless administered as a fixed-dose combination with a potassium conserving drug or changed to potassium sparing agent before the screening), nonselective β-blocking drugs, quinidine, quinidine like anti-arrhythmic, or any medication with a QTc prolongation potential or a history of QTc prolongation
Subjects treated with monoamine oxidase inhibitors (MAOIs) and tricyclic anti-depressants
Subjects receiving any therapy that could interfere with the study drugs according to Investigator’s opinion
Participation in an investigational trial: Subjects who have received an investigational drug within 2 months or six half-lives (whichever is greater) prior to screening visit, or have been previously randomised in this trial, or are currently participating in another clinical trial
Documented coronavirus disease 2019 (COVID-19) diagnosis within the last 2 weeks, or associated complications/symptoms, which have not resolved within 14 days prior to screening or randomization
Vaccination: Subjects having received a vaccination within 2 weeks prior to screening or during the run-in period
For females only: pregnant or lactating women, where pregnancy is defined as the state of a female after conception and until termination of the gestation, confirmed by a positive serum human chorionic gonadotropin (β-HCG) laboratory test

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Bulgaria	Not Recruiting	01 Nov 2023	77
Czechia	Not Recruiting	01 Nov 2023	32
Germany	Not Recruiting	01 Nov 2023	54
Hungary	Not Recruiting	01 Nov 2023	39
Italy	Not Recruiting	01 Nov 2023	19
Latvia	Not Recruiting	01 Nov 2023	32
Lithuania	Not Recruiting	01 Nov 2023	13
Poland	Not Recruiting	01 Nov 2023	75
Romania	Not Recruiting	01 Nov 2023	18
Spain	Not Recruiting	01 Nov 2023	18